Neuropathic pain consists of peripheral neuropathic pain and central neuropathic pain (U.S. Pat. No. 6,211,171). Various factors such as obstructions of various peripheral nerves, nerve root, spinal cord or a part of brain, infection of virus such as herpes virus (herpes zoster), and use of an anticancer agent induce variety of neuropathic pains such as allodynia, hyperalgesia, and prolonged response duration. Inflammations such as rheumatism and gout are also frequently accompanied by severe pain. Diabetic pain, post-herpes zoster pain, fiber muscle pain, and restless legs syndrome are also considered to be neuropathic diseases. Itch also has characteristics very similar to those of pain. Therapeutic treatments of these neuropathic diseases often encounters difficulty.
Gabapentin and pregabalin, which can be regarded as derivatives of gamma-aminobutyric acid (GABA), are used as an anti-epileptic that acts on the central nerve system, and they are also used for therapeutic treatments of pain or discomfort in the aforementioned neuropathic diseases (WO98/03167). Although the mode of action of these agents has not been fully elucidated, it is estimated that they bind with the α2δ subunit of the voltage-dependent-calcium channel to exhibit the efficacy (it is considered, however, that they do not act on the gaba receptor in the brain).
These agents are usually used as an oral agent, and when they are used for therapeutic treatment of pain, they are orally administered at a daily dose of 200 to 2,400 mg for gabapentin or 150 to 600 mg for pregabalin, or they sometimes may be administered at a still higher dose. Since these agents highly frequently cause side reactions concerning the central nerve system such as lethargy and vertigo even at a usual dose, as well as the case of using such high doses as mentioned above, these side reactions are most serious problems in the therapeutic treatment of pain.
For the therapeutic treatment of pain accompanying these diseases, besides a treatment based on systemic administration such as oral administration, a method of suppressing transfer of pain by local administration may also be contemplated. Pain is not necessarily felt equally in the whole body, and severe pain is locally felt in many cases. Therefore, when an analgesic effect can be attained by local administration, a therapeutic treatment can be realized with reduced side reactions by means of a lowered dose and the like. For example, local administration is effective in the therapeutic treatment of pain with a tricyclic compound antidepressant (U.S. Pat. No. 6,211,171), and a local anesthetic, of which typical example is lidocaine, is effective for therapeutic treatment of local pain. Local administration of a non-steroidal anti-inflammatory agent suppresses inflammation, and thereby ameliorates pain. Concerning local administration of these local anesthetics and the like, there are reports such as by Hind Harry (EP0388306), Gammaitoni et al. (J. Clin. Pharmaco., 2003, 43 (2), pp. 111-117).
An analgesic action may possibly be attained by local administration of pregabalin or gabapentin as an external preparation at a site of pain. However, in order to effectively attain an analgesic action with pregabalin or gabapentin, absorption of at least a certain amount of the drug is considered to be essential. Even if a percutaneous absorption system including various devices for the above purpose is used, a daily dose is limited. Moreover, if absorption is enhanced so as to obtain a high blood concentration, the same side reactions as those induced by oral administration will be induced. Although gabapentin and pregabalin are highly water-soluble, a water-soluble agent generally achieves poor percutaneous absorption, and is considered to be unsuitable for external use.
With regard to application of gabapentin to therapeutic treatment of neuropathic pain, Carlton et al. reported that subcutaneous administration of gabapentin was effective for suppressing pain in an animal model, and effective for the peripheral system (Pain, 1998, 76, pp. 201-207). There has been proposed a method of externally applying these agents in combination with other agents for analgesic purpose (EP1940352). For this administration scheme, various pharmaceutical compounds are exemplified for use in an aqueous preparation characterized by containing hydroxypropylmethylcellulose, and gabapentin and pregabalin are mentioned as mere examples among the various pharmaceutical compounds.
There is an example of use of a cetylated fatty acid ester as a percutaneous absorption enhancer (U.S. Patent Published Application No. 2011/0065627). As an example of pharmaceutical devising, it was reported that a preparation of pregabalin (and combination of pregabalin and diclofenac, International Journal of Pharmaceutical Compounding, 2003, 7, pp. 180-183) suppressed pain due to neuropathic orofacial pain in rats, and the infraoebital nerve territory in the vibrissae area was chosen as the administration site in order to obtain a higher blood concentration (Oral Medicine, 2012, 114, pp. 449-456). U.S. Pat. No. 6,572,880 (Murdock) disclosed that administration of a pharmaceutical preparation obtained in the presence of propylene glycol and soybean lecithin using a Luer Loc syringe provided remission of spastic tetraplegia induced by traumatic injury over one week. International Patent Publication WO2008/067991 reported that an amine compound formed a complex with an acrylic acid polymer to generally increase absorption of the agent, and gabapentin is mentioned as an example of such agent. Cundy et al. devised a percutaneous absorption system to develop an external preparation of a prodrug of gabapentin or pregabalin (International Patent Publication WO2005/089872).